Endocrine Abstracts

Introduction: Isolated Gonadotropin Releasing Hormone (GnRH) Deficiency (IGD) is a rare disease with a wide spectrum of reproductive and non- reproductive clinical characteristics and is mainly characterized by hypogonadotropic hypogonadism with anosmia (Kallmann Syndrome) or normal olfactory function (Normosmic Idiopathic Hypogonadotropic Hypogonadism- nIHH). Apart from the phenotypic heterogeneity IGD is also highly genetically heterogeneous with >35 genes implicated in the disease. Despite this genetic heterogeneity, genetic enrichment in specific subpopulations has been described.

Methods: A cohort of 87 IGD patients underwent Sanger and Whole Exome Sequencing (WES) with the goal to discover rare sequence variants (RSVs) in genes that cause IGD. Sanger sequencing was performed in 14 known IGD genes, whereas WES expanded the analysis to 37 genes. All patients were phenotyped in detail and segregation of the detected variants was performed in family members via Sanger Sequencing.

Results: The cohort consisted of 58 male and 29 female probands and was represented by a large number of normosmic patients (57 nIHH probands) compared to patients with Kallmann Syndrome (30 probands) suggestive of a phenotypic enrichment of the normosmic feature. The majority of cases were sporadic (79/87) and most patients carried non- reproductive features. Even though, Sanger sequencing detected RSVs in 25% (21/81) of IGD patients in 7/14 IGD genes without any evidence of oligogenicity, WES revealed that 31% (27/87) of IGD patients carried a rare genetic change in a total of 15 genes with 4 IGD cases being oligogenic (i.e. carrying RSVs in more than 1 genes).

Discussion: This is the first analysis on the largest IGD Greek cohort that has ever being studied. Our findings suggest that next generation sequencing (NGS) techniques can discover previously undetected variation, making them the standardized method for screening patients with rare and/or more common disorders.